The broad and long term objective of this proposal is to improve antibiotic therapy of bacterial infections by delivering high concentrations of drug to the site of action while bypassing other tissues, thereby increasing the effectiveness of the drug and decreasing its potential for toxicity. Liposomal entrapped antibiotics have shown promise in terms of enhancing intracellular killing of bacteria, reducing systemic toxicity and increasing efficacy in immunocompromised patients. The importance of optimizing antimicrobial activity in immunocompromised patients has steadily grown with the advent of AIDS and the increasing number of neutropenic patients. These patients are very susceptible to recurrent infections. These recurrent infections are often caused by facultative bacteria which are able to colonize macrophages after phagocytosis. Since liposomes are predominantly distributed to the RES, liposome antibiotic formulations should enhance the bactericidal activity of antibiotics. These studies will firstly determine the influence of liposomal encapsulation on the disposition and efficacy of cephalosporins and secondly determine the influence of circulating and tissue macrophages on the disposition of liposomal entrapped drug. The specific aims of this project are 1) to develop a liposomal formulation for cephalosporins which will increase intracellular concentrations of active drug and thus increase bactericidal efficacy; 2) to determine the influence of liposomal entrapment of cephalosporins on tissue distribution, volume of distribution, and renal and hepatic routes of elimination and 3) to determine the bactericidal efficacy of both free and liposomal entrapped antibiotic in the treatment of intracellular and extracellular infections. In vitro uptake and efficacy studies will be used to test the liposome formulation to optimize uptake and antibacterial efficacy. The optimal formulation(s) will be tested in vivo to determine its pharmacokinetic/pharmacodynamic properties. Specifically, the influence of circulating macrophages on tissue distribution and bactericidal efficacy will be determined by testing the liposome entrapped drug in both immune competent and neutropenic animals. To ascertain the influence of liposomal encapsulation on the clearance of drug from the body will be determined by examining cephalosporins which are cleared from the body by different elimination pathways.